This is a proposal to investigate the mechanisms underlying 20-hydroxyeicosatetraenoic acid (20-HETE)- mediated androgen-induced (male-specific) hypertension. Hypertension is a complex process that involves cardiac output and total peripheral resistance, which is mainly manifested by the small arteries and arterioles due to increase in smooth muscle constriction, endothelial dysfunction, and endothelial activation. 20-HETE is a primary eicosanoid in the microcirculation where it participates in the regulation of vascular tone by sensitizing the smooth muscle cells to constrictor stimuli and contributes to myogenic, mitogenic and angiogenic responses. We have demonstrated that androgen-induced hypertension in rats is driven by increased synthesis of 20-HETE in the vasculature. Moreover, renal arteries from androgen treated-rats displayed endothelial dysfunction that is characterized by reduction in NO bioavailability. In vitro, 20- HETE causes endothelial dysfunction via eNOS uncoupling and endothelial activation (increased inflammatory cytokines) via NFkB activation. These findings suggest that vascular 20-HETE is an important determinant of androgen-induced hypertension through action on both endothelial dysfunction and endothelial activation and are the basis for our working hypothesis: Androgen-induced hypertension is mediated by increased vascular 20-HETE, which, in turn, induces endothelial dysfunction and endothelial activation, each of which contributes to the genesis of hypertension. To this end, it is unclear whether the activation of both pathways by 20-HETE is required simultaneously to produce hypertension or whether a single pathway is either sufficient or more dominant. This proposal will discern the temporal relationship between these two processes and will examine the contribution of each to 20-HETE-mediated male-specific hypertension using 1) pharmacological (enzyme inhibitors) and molecular/genetic (viral vectors and transgenic mouse models) to inhibit or induce the synthesis of 20-HETE; and 2) inhibitors of NFkB activation and transgenic mice in which NFkB activation is impaired to determine whether androgen-induced, 20- HETE-driven hypertension is co-dependent upon both endothelial activation and dysfunction. It is recognized that men are at greater risks for hypertension and cardiovascular disease than women and that androgen plays an important role. The proposed studies have the potential of providing insights into mechanisms underlying the increase prevalence of hypertension and susceptibility to cardiovascular morbidity in male and thereby uncovering a novel therapeutic target for the treatment of hypertension driven by increased androgen levels.